Emergence of antimicrobial resistance is an ever-increasing threat to our ability to treat a wide range of infections caused by microbes that thwart or block antimicrobial therapy. Staphylococcus aureus, an organism frequently resistant to multiple antibiotics, is an important early cause of infectious morbidity in children with cystic fibrosis (CF), usually occurring before infection with Pseudomonas aeruginosa. Since oropharygeal carriage of S aureus generally precedes infection of the lower airways, eradication of this organism from the throat is of major clinical importance to children with CF. Current strategies, particularly use of antibiotics, often lead to antimicrobial resistance, side effects and relapse. Probiotics, particularly Lactobacillus GG (LGG) are capable of killing various bacteria, including S aureus and P aeruginosa, in vitro, by a variety of mechanisms. Preliminary data from one small study in healthy volunteers suggests that LGG may be able to eradicate nasal carriage of S aureus, although effects on oropharygeal carriage is unknown. We propose to conduct a pilot double-blind randomized placebo controlled clinical trial to refine methodology and determine feasibility of evaluating whether orally administered LGG is effective in eliminating oropharygeal colonization with S aureus in children with CF, without emergence of colonization with P aeruginosa. If safe and effective, LGG may provide an alternative way to eliminate this bacteria without use of antimicrobials that risk emergence of resistant organisms. Forty CF patients will be recruited into the study, 30 will receive oral LGG, 10 will receive matching oral placebo. The specific aims are to: (1) refine methods of administering probiotics and matching placebo, in preparation for future studies that will investigate effects of probiotics on eradication of throat carriage of S aureus; (2) collect pilot data on elimination of oropharyngeal colonization with S aureus to power future studies that will evaluate whether LGG is an effective alternative to antimicrobials; and (3) determine whether LGG colonizes the oropharynx as a first step to exploring potential mechanisms by which LGG may influence mucosal Staphylococcus aureus colonization and (4) explore effects on clinical status (weight gain and pulmonary function). This study has the potential to provide insight into a novel alternative approach to eradicate and prevent the spread of antimicrobial resistant pathogens.